The objectives of these studies are to clarify the mechanism of the cerebral microcirculatory alterations following experimental fluid-percussion brain injury in anesthetized cats and in rabbits. This type of brain injury induces pial arteriolar dilation associated with a reduced responsiveness to the vasoconstrictor effects of arterial hypocapnia and with disturbed autorregulatory dilation in response to arterial hypotension. The vessels which showed these abnormalities have lesions in their vascular smooth muscle and endothelium, and display reduced oxygen consumption. The proposed studies will test the hypothesis that these abnormalities are mediated by free oxygen radicals generated in association with accelerated arachidonate metabolism via cyclooxygenase. The proposed experiments are designed to identify the factors which influence superoxide anion radical generation after brain injury, to determine whether superoxide anion radical generated by brain injury traverses the cell membrane via the anion channel, to identify the enzymatic sources of superoxide, including cyclooxygenase, lipoxygenase, cytochrome P450 reductase and xanthine oxidase, to examine whether substance P, enkephalins or bradykinin initiate the sequence which leads to superoxide production, to examine the effects of oxygen radicals on the blood-brain barrier and to determine whether endothelium-dependent vasodilator reponses are disturbed after brain injury.